Section 23.2.1. Introduction

There are currently over a thousand unique protein-bound ligands described in the Protein Data Bank, illustrating the enormous variety of small molecules with which proteins interact. These ligands serve as cofactors in protein-mediated reactions, substrates in these reactions, and elements that maintain or alter protein structure or macromolecular assembly. The specific binding of small molecules to proteins is a primary means by which living systems interact and exchange information with their environment. The atomic details of protein–ligand interactions are often quite similar to the intramolecular interactions observed within a protein molecule. Examples of all the various non-covalent interactions described in Parts 20 and 22 , such as hydrogen bonds, van der Waals forces and other electrostatic phenomena, are observed between proteins and their small-molecule ligands.

Through the diverse interactions observed between proteins and their ligands, a few fundamental patterns of recognition emerge. In general, ligand binding requires that the protein partially or fully sequesters the ligand from the solvent. This demands that the energy of interaction between the protein and the ligand must be strong enough to overcome the interactions between both species and the solvent as well as the translational and rotational entropy which is lost upon fixing the orientation of the ligand relative to the protein. The protein achieves this level of interaction by presenting a binding site that is complementary to the ligand both in shape and electrostatic functionality. Beyond this generalization, each ligand has its own unique and complicated story. Rather than attempt to summarize the enormous subject of protein–ligand interactions in a comprehensive manner, we will instead illustrate several of the unique interactions observed between proteins and other molecules.